The long range objectives of our research are to: 1) understand the mechanisms by which microcirculatory structure is regulated in normal and pathological conditions (especially hypertension), and 2) evaluate the impact of structural changes on microvascular resistance and microcirculatory function. One of the most striking changes that occurs in some organs in hypertension is microvascular rarefaction, i.e., a substantial loss of arterioles and capillaries which is mediated via structural degeneration of the vessels. Recent studies by our group indicate that microvascular rarefaction may also occur in response to elevated salt intake. A widespread rarefaction of microvessels could contribute to the elevated peripheral vascular resistance in chronic hypertension, and may have important implications for tissue perfusion in key target organs such as the heart and brain. Furthermore, a permanent reduction in vessel density mediated by structural degeneration of microvessels could have significant implications for the treatment of hypertension, since it may lead to a sustained elevation in vascular resistance and alterations in tissue perfusion which would be refractory to therapy with vasodilator agents. However, the extent of microvascular rarefaction in different organs, the ability of microvascular rarefaction to be reversed, and the relative contribution of rarefaction to an elevated microvascular resistance and altered tissue perfusion remains to be determined. In the present project, we propose to specifically investigate both the mechanisms and the consequences of microvascular rarefaction. The central working hypothesis of the project is that rarefaction is a continuous degenerative process that occurs in multiple vascular beds during hypertension and elevated salt intake, and that rarefaction leads to significant alterations in microcirculatory function. It is further hypothesized that the reduction in vessel density occurring during renovascular hypertension or elevated salt intake is mediated via one or a combination of several factors including: 1) elevated microvascular pressure, 2) reduced plasma angiotensin II levels, or 3) sympathetic nervous input. The specific aims of this project are to: 1) determine the mechanisms by which hypertension and elevated salt intake lead to vessel loss; 2) determine the extent of rarefaction in different organs in hypertension and during elevated salt intake; 3) to determine whether rarefaction is reversible; 4) determine whether rarefaction contributes to an elevated microvascular resistance, and 5) determine whether the structural changes occurring during renovascular hypertension and elevated salt intake alter tissue PO2 distribution and arteriolar responses to vasoactive agonists. These aims will be investigated via acute and chronic experiments and histological studies in reduced renal mass hypertensive rats and normotensive rats on high and low salt diets.